A Wearable Upper Limb Exoskeleton System and Intelligent Control Strategy.

Heavy lifting operations frequently lead to upper limb muscle fatigue and injury. In order to reduce muscle fatigue, auxiliary force for upper limbs can be provided. This paper presents the development and evaluation of a wearable upper limb exoskeleton (ULE) robot system. A flexible cable transmits auxiliary torque and is connected to the upper limb by bypassing the shoulder. Based on the K-nearest neighbors (KNN) algorithm and integrated fuzzy PID control strategy, the ULE identifies the handling posture and provides accurate active auxiliary force automatically. Overall, it has the quality of being light and easy to wear. In unassisted mode, the wearer's upper limbs minimally affect the range of movement. The KNN algorithm uses multi-dimensional motion information collected by the sensor, and the test accuracy is 94.59%. Brachioradialis muscle (BM), triceps brachii (TB), and biceps brachii (BB) electromyogram (EMG) signals were evaluated by 5 kg, 10 kg, and 15 kg weight conditions for five subjects, respectively, during lifting, holding, and squatting. Compared with the ULE without assistance and with assistance, the average peak values of EMG signals of BM, TB, and BB were reduced by 19-30% during the whole handling process, which verified that the developed ULE could provide practical assistance under different load conditions.

A Fusion Network with Stacked Denoise Autoencoder and Meta Learning for Lateral Walking Gait Phase Recognition and Multi-Step-Ahead Prediction.

Lateral walking gait phase recognition and prediction are the premise of hip exoskeleton application in lateral resistance walk exercise. In this work, we presented a fusion network with stacked denoise autoencoder and meta learning (SDA-NN-ML) to recognize gait phase and predict gait percentage from IMU signals. Experiments were conducted to detect the four lateral walking gait phases and predict their percentage in 10 healthy subjects across different speeds. The performance of SDA-NN-ML and other widely used algorithms including Support Vector Machine (SVM), Adaptive Boosting (AdaBoost) and Long Short Term Memory (LSTM) were evaluated. The cross-subject recognition accuracy of SDA-NN-ML (89.94%) decreased by 4.62% compared to the training accuracy, which outperformed SVM (8.60%), AdaBoost (5.61%), and LSTM (7.12%). For real-time and cross-subject prediction of gait phase percentage, the RMSE of SDA-NN-ML (0.2043) outperformed that of a single regression network (0.2426). With a signal noise ratio of 100:30, the cross-subject recognition accuracy decreased by a mere 5.70%, while the prediction result (RMSE) of SDA-NN-ML increased by 0.0167 when compared to the noise-free results. SDA-NN-ML demonstrates a stable multi-step-ahead prediction ability with an accuracy higher than 82.50% and an RMSE of less than 0.23 when the ahead time is less than 200 ms. The results demonstrated that the proposed method has high accuracy and robust performance in lateral walking gait recognition and prediction.

Continuous Locomotion Mode and Task Identification for an Assistive Exoskeleton Based on Neuromuscular-Mechanical Fusion.

Human walking parameters exhibit significant variability depending on the terrain, speed, and load. Assistive exoskeletons currently focus on the recognition of locomotion terrain, ignoring the identification of locomotion tasks, which are also essential for control strategies. The aim of this study was to develop an interface for locomotion mode and task identification based on a neuromuscular-mechanical fusion algorithm. The modes of level and incline and tasks of speed and load were explored, and seven able-bodied participants were recruited. A continuous stream of assistive decisions supporting timely exoskeleton control was achieved according to the classification of locomotion. We investigated the optimal algorithm, feature set, window increment, window length, and robustness for precise identification and synchronization between exoskeleton assistive force and human limb movements (human-machine collaboration). The best recognition results were obtained when using a support vector machine, a root mean square/waveform length/acceleration feature set, a window length of 170, and a window increment of 20. The average identification accuracy reached 98.7% ± 1.3%. These results suggest that the surface electromyography-acceleration can be effectively used for locomotion mode and task identification. This study contributes to the development of locomotion mode and task recognition as well as exoskeleton control for seamless transitions.

Phenotypic diversity observed in a Chinese patient cohort with biallelic variants in Bardet-Biedl syndrome genes.

PURPOSE: Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy. The aim of this study was to describe the clinical and genetic features of a cohort of Chinese patients carrying biallelic BBS gene variants. METHODS: We recruited 34 patients from 31 unrelated pedigrees who carried biallelic pathogenic variants in BBS genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Ultimately, 14 patients were followed up over time. RESULTS: We identified 47 diseasing-causing variants in 10 BBS genes; 33 were novel. Diagnosis of BBS and non-syndromic retinitis pigmentosa (RP) were established in 28 patients from 27 pedigrees and 6 patients, respectively. The two most prevalent genes in patients with BBS were BBS2 and BBS4, accounting for 51.8% of the probands. The patients exhibited clinical heterogeneity, from patients with all six primary clinical components to patients suffering from non-syndromic RP. The common components were retinal dystrophy, polydactyly, and obesity, with frequencies of 78.6% to 100%, while renal anomaly frequencies were only 7.1%. Patients exhibited early and severe visual defects and retinal degeneration. Patients with biallelic missense variants in BBS2 suffered fewer clinical symptoms and mild visual impairment. Patients with BBS10 variants tended to have cone dystrophy. CONCLUSIONS: Our study defined the mutated gene profiles and established the configuration of the variation frequencies for each BBS gene in Chinese patients. Overall, our patients showed early and severe visual defects and retinal degeneration. Genetic analysis is therefore crucial for diagnosis, genetic counseling, and future gene therapy in these patients.

Brassica napus BnaC9.DEWAX1 Negatively Regulates Wax Biosynthesis via Transcriptional Suppression of BnCER1-2.

Very-long-chain alkane plays an important role as an aliphatic barrier. We previously reported that BnCER1-2 was responsible for alkane biosynthesis in Brassica napus and improved plant tolerance to drought. However, how the expression of BnCER1-2 is regulated is still unknown. Through yeast one-hybrid screening, we identified a transcriptional regulator of BnCER1-2, BnaC9.DEWAX1, which encodes AP2\ERF transcription factor. BnaC9.DEWAX1 targets the nucleus and displays transcriptional repression activity. Electrophoretic mobility shift and transient transcriptional assays suggested that BnaC9.DEWAX1 repressed the transcription of BnCER1-2 by directly interacting with its promoter. BnaC9.DEWAX1 was expressed predominantly in leaves and siliques, which was similar to the expression pattern of BnCER1-2. Hormone and major abiotic stresses such as drought and high salinity affected the expression of BnaC9.DEWAX1. Ectopic expression of BnaC9.DEWAX1 in Arabidopsis plants down-regulated CER1 transcription levels and resulted in a reduction in alkanes and total wax loads in leaves and stems when compared with the wild type, whereas the wax depositions in the dewax mutant returned to the wild type level after complementation of BnaC9.DEWAX1 in the mutant. Moreover, both altered cuticular wax composition and structure contribute to increased epidermal permeability in BnaC9.DEWAX1 overexpression lines. Collectively, these results support the notion that BnaC9.DEWAX1 negatively regulates wax biosynthesis by binding directly to the BnCER1-2 promoter, which provides insights into the regulatory mechanism of wax biosynthesis in B. napus.

Clinical and genetic findings in a Chinese cohort with choroideremia.

OBJECTIVE: Choroideremia (CHM) is an X-linked chorioretinal dystrophy caused by variants in the CHM gene. The aim of this study was to report the clinical and genetic features of a cohort of affected males with CHM and establish the relationship between best correct visual acuity (BCVA) and age. METHOD: Twenty-seven patients from 24 unrelated families underwent detailed ophthalmic examinations and comprehensive molecular genetic analysis. We combined the 27 patients in our own cohort with 68 Chinese patients from six previously reported studies to determine a transition age for BCVA rapid decline in 95 patients. RESULTS: Twenty-three causal (9 novel) CHM variants were identified in the 27 patients, who had a mean age of 30.5 ± 17.4 years and a mean BCVA (LogMAR) of 0.61 ± 0.79. Patients at different disease stages showed different extents of retinal pigment epithelium (RPE) and choroid abnormalities. Central retinal optical coherence tomography (OCT) scanning revealed defects in the ellipsoid zone and RPE in all patients and outer retinal tubulations in 75%. The 95 patients had a mean age of 33.27 ± 16.27 years and an average (LogMAR) of 0.72 ± 0.82. The BCVA did not decline rapidly before age 25, but decreased at a mean rate of 0.037logMAR/year after that age. CONCLUSIONS: Our results indicated Chinese patients with CHM variants have a younger transition age for rapid BCVA decline than previously reported for other ethnic groups. Central retinal OCT scanning can identify different abnormalities in the retinal structures, and these might be used as other parameters for monitoring disease progression in patients with CHM.

Phenotype-Based Genetic Analysis Reveals Missing Heritability of ABCA4-Related Retinopathy: Deep Intronic Variants and Copy Number Variations.

Purpose: To identify the missing heritability of ABCA4-related retinopathy in a Chinese cohort. Methods: We recruited 33 unrelated patients with ABCA4-related retinopathy carrying a monoallelic variant in ABCA4. All patients underwent ophthalmic examinations. Next-generation sequencing of the whole ABCA4 sequence, including coding and noncoding regions, was performed to detect deep intronic variants (DIVs) and copy number variations (CNVs). Results: We identified eight missing pathogenic ABCA4 variants in 60.6% of the patients (20/33), which comprised five DIVs and three CNVs. The five DIVs, including four novel (c.1555-816T>G, c.2919-169T>G, c.2919-884G>T, and c.5461-1321A>G) and one reported (c.4539+1100A>G), accounted for the missing alleles in 51.5% of the patients. Minigene assays showed that four novel DIVs activated cryptic splice sites leading to the insertions of pseudoexons. The three novel CNVs consisted of one gross deletion of 1273 bp (exon 2) and two gross duplications covering 25.2 kb (exons 28-43) and 9.4 kb (exons 38-44). The microhomology domains were identified at the breakpoints and revealed the potential mechanisms of CNV formation. Conclusions: DIVs and CNVs explained approximately two-thirds of the unresolved Chinese cases with ABCA4-related retinopathy. Combining results from phenotypic-directed screening, targeting the whole ABCA4 sequencing and in silico tools can help to identify the missing heritability.

Hardware Circuits Design and Performance Evaluation of a Soft Lower Limb Exoskeleton.

Soft lower limb exoskeletons (LLEs) are wearable devices that have good potential in walking rehabilitation and augmentation. While a few studies focused on the structure design and assistance force optimization of the soft LLEs, rarely work has been conducted on the hardware circuits design. The main purpose of this work is to present a new soft LLE for walking efficiency improvement and introduce its hardware circuits design. A soft LLE for hip flexion assistance and a hardware circuits system with scalability were proposed. To assess the efficacy of the soft LLE, the experimental tests that evaluate the sensor data acquisition, force tracking performance, lower limb muscle activity and metabolic cost were conducted. The time error in the peak assistance force was just 1%. The reduction in the normalized root-mean-square EMG of the rectus femoris was 7.1%. The net metabolic cost in exoskeleton on condition was reduced by 7.8% relative to walking with no exoskeleton. The results show that the designed hardware circuits can be applied to the soft LLE and the soft LLE is able to improve walking efficiency of wearers.

A Portable Waist-Loaded Soft Exosuit for Hip Flexion Assistance with Running.

The soft exosuit is an emerging robotics, which has been proven to considerably reduce the metabolic consumption of human walking and running. However, compared to walking, relatively few soft exosuits have been studied for running. Many soft exosuits used for running are worn on the back and with a heavy weight load, which may cause instability while running and potentially increase metabolic consumption. Therefore, reducing the weight of the whole soft exosuit system as much as possible and keeping the soft exosuit close to the center of gravity, may improve running stability and further reduce metabolic consumption. In this paper, a portable waist-loaded soft exosuit, the weight of which is almost entirely concentrated at the waist, is shown to assist hip flexion during running, and justifies choosing to assist hip flexion while running. As indicated by the experiments of motion flexibility, wearing the waist-loaded soft exosuit can assist in performing many common and complex motions. The metabolic consumption experiments proved that the portable waist-loaded soft exosuit reduces the metabolic consumption rate of wearers when jogging on the treadmill at 6 km per hour by 7.79% compared with locomotion without the exosuit. Additionally, at the running speed of 8 km per hour, using the waist-loaded soft exosuit can reduce metabolic consumption rate by 4.74%. Similarly, at the running speed of 10 km per hour, it also can be reduced by 6.12%. It is demonstrated that assisting hip flexion for running is also a reasonable method, and wearing the waist-loaded soft exosuit can keep human motion flexibility and reduce metabolic consumption.

A Time Division Multiplexing Inspired Lightweight Soft Exoskeleton for Hip and Ankle Joint Assistance.

Exoskeleton robots are frequently applied to augment or assist the user's natural motion. Generally, each assisted joint corresponds to at least one specific motor to ensure the independence of movement between joints. This means that as there are more joints to be assisted, more motors are required, resulting in increasing robot weight, decreasing motor utilization, and weakening exoskeleton robot assistance efficiency. To solve this problem, the design and control of a lightweight soft exoskeleton that assists hip-plantar flexion of both legs in different phases during a gait cycle with only one motor is presented in this paper. Inspired by time-division multiplexing and the symmetry of walking motion, an actuation scheme that uses different time-periods of the same motor to transfer different forces to different joints is formulated. An automatic winding device is designed to dynamically change the loading path of the assistive force at different phases of the gait cycle. The system is designed to assist hip flexion and plantar flexion of both legs with only one motor, since there is no overlap between the hip flexion movement and the toe-offs movement of the separate legs during walking. The weight of the whole system is only 2.24 kg. PD iterative control is accomplished by an algorithm that utilizes IMUs attached on the thigh recognizing the maximum hip extension angle to characterize toe-offs indirectly, and two load cells to monitor the cable tension. In the study of six subjects, muscle fatigue of the rectus femoris, vastus lateralis, gastrocnemius and soleus decreased by an average of 14.69%, 6.66%, 17.71%, and 8.15%, respectively, compared to scenarios without an exoskeleton.

Biomechanical and Physiological Evaluation of a Multi-Joint Exoskeleton with Active-Passive Assistance for Walking.

How to improve the walking efficiency while ensuring the wearability is an important issue of lower limb exoskeletons. Active devices can provide greater forces, while the passive devices have advantage in weight. We presented a multi-joint exoskeleton with active hip extension assistance and passive ankle plantarflexion assistance in this work. An admittance controller based on a feedforward model was proposed to track the desired active force of the hip extension. An underfoot clutch mechanism was adapted to realize the passive ankle plantarflexion assistance. To assess the efficacy of the multi-joint exoskeleton in assisting walking, we conducted comprehensive experiments to evaluate the force tracking performance, lower limb muscle activities and metabolic cost. The results demonstrated that: (i) The average tracking error of the peak hip extension assistance force from three subjects was less than 3%. (ii) The reductions of normalized root-mean-square EMG in the lateral soleus, medial soleus and gluteus maximus of eight subjects achieved 15.33%, 11.11%, and 3.74%, respectively. (iii) The average metabolic cost of six subjects was reduced by 10.41% under exoskeleton on (EO) condition comparing to the condition of walking with no exoskeleton (NE). This work proved that the concept of the multi-joint exoskeleton with active-passive assistance can improve the walking efficiency.

A Novel Lightweight Wearable Soft Exosuit for Reducing the Metabolic Rate and Muscle Fatigue.

Wearable robotic devices have been proved to considerably reduce the energy expenditure of human walking. It is not only suitable for healthy people, but also for some patients who require rehabilitation exercises. However, in many cases, the weight of soft exosuits are relatively large, which makes it difficult for the assistant effect of the system to offset the metabolic consumption caused by the extra weight, and the heavy weight will make people uncomfortable. Therefore, reducing the weight of the whole system as much as possible and keeping the soft exosuit output power unchanged, may improve the comfort of users and further reduce the metabolic consumption. In this paper, we show that a novel lightweight soft exosuit which is currently the lightest among all known powered exoskeletons, which assists hip flexion. Indicated from the result of experiment, the novel lightweight soft exosuit reduces the metabolic consumption rate of wearers when walking on the treadmill at 5 km per hour by 11.52% compared with locomotion without the exosuit. Additionally, it can reduce more metabolic consumption than the hip extension assisted (HEA) and hip flexion assisted (HFA) soft exosuit which our team designed previously, which has a large weight. The muscle fatigue experiments show that using the lightweight soft exosuit can also reduce muscle fatigue by about 10.7%, 40.5% and 5.9% for rectus femoris, vastus lateralis and gastrocnemius respectively compared with locomotion without the exosuit. It is demonstrated that decreasing the weight of soft exosuit while maintaining the output almost unchanged can further reduce metabolic consumption and muscle fatigue, and appropriately improve the users' comfort.

A Semi-active Exoskeleton Based on EMGs Reduces Muscle Fatigue When Squatting.

In dynamic manufacturing and warehousing environments, the work scene made it impossible for workers to sit, so workers suffer from muscle fatigue of the lower limb caused by standing or squatting for a long period of time. In this paper, a semi-active exoskeleton used to reduce the muscle fatigue of the lower limb was designed and evaluated. (i) Background: The advantages and disadvantages of assistive exoskeletons developed for industrial purposes were introduced. (ii) Simulation: The process of squatting was simulated in the AnyBody.7.1 software, the result showed that muscle activity of the gluteus maximus, rectus femoris, vastus medialis, vastus lateralis, vastus intermedius, and erector spinae increased with increasing of knee flexion angle. (iii) Design: The exoskeleton was designed with three working modes: rigid-support mode, elastic-support mode and follow mode. Rigid-support mode was suitable for scenes where the squatting posture is stable, while elastic-support mode was beneficial for working environments where the height of squatting varied frequently.The working environments were identified intelligently based on the EMGs of the gluteus maximus, and quadriceps, and the motor was controlled to switch the working mode between rigid-support mode and elastic-support mode. In follow mode, the exoskeleton moves freely with users without interfering with activities such as walking, ascending and descending stairs. (iv) Experiments: Three sets of experiments were conducted to evaluate the effect of exoskeleton. Experiment one was conducted to measure the surface electromyography signal (EMGs) in both condition of with and without exoskeleton, the root mean square of EMGs amplitude of soleus, vastus lateralis, vastus medialis, gastrocnemius, vastus intermedius, rectus femoris, gluteus maximus, and erector spinae were reduced by 98.5, 97.89, 80.09, 77.27, 96.73, 94.17, 70.71, and 36.32%, respectively, with the assistance of the exoskeleton. The purpose of experiment two was aimed to measure the plantar pressure with and without exoskeleton. With exoskeleton, the percentage of weight through subject's feet was reduced by 63.94, 64.52, and 65.61% respectively at 60°, 90°, and 120° of knee flexion angle, compared to the condition of without exoskeleton. Experiment three was purposed to measure the metabolic cost at a speed of 4 and 5 km/h with and without exoskeleton. Experiment results showed that the average additional metabolic cost introduced by exoskeleton was 2.525 and 2.85%. It indicated that the exoskeleton would not interfere with the movement of the wearer Seriously in follow mode. (v) Conclusion: The exoskeleton not only effectively reduced muscle fatigue, but also avoided interfering with the free movement of the wearer.

A soft exosuit for hip extension assistance of the elderly.

BACKGROUND: Population aging is now a universal trend. Many elderly persons can only conduct limited and short time walking because of age-related skeletal muscle decline of the lower limbs. The wearable device for walking assistance is beneficial to improve the life quality of the elderly. OBJECTIVE: This study aimed to propose a soft exosuit for walking assistance of the elderly and verify its feasibility. METHODS: The wearable structure and control strategy were presented. The performance of the soft exosuit was tested by force tracking evaluation and metabolic cost test. RESULTS: The mean error of the measured and target peak force was 1.1%. The metabolic cost with assistance on while wearing the exosuit was reduced by 9.2% compared with that in locomotion assistance off. The reduction of assistance on was 7.1% compared with no exosuit. CONCLUSIONS: The proposed soft exosuit has the potential to improve the walking efficiency of the elderly.

Voice controlled wheelchair integration rehabilitation training and posture transformation for people with lower limb motor dysfunction.

BACKGROUND: Stroke and other neurological disorders have an effect on mobility, which has a significant impact on independence and quality of life. The core rehabilitation requirements for patients with lower limb motor dysfunction are gait training, re-stand and mobility. OBJECTIVE: A wheelchair called ReChair was invented that seamlessly integrated mobility, gait training and multi-posture transformation with voice control. METHODS: The mechanical structure and control system of ReChair were designed. The overall evaluation included voice recognition and balance training test to quantitatively verify the performance of ReChair. RESULTS: The average success recognition rate of posture transformation by voice control can reach 91% to 96% in a quiet environment (20-30 DB). The balance training game is easy to operate and the score can be used as a quantified guideline for rehabilitation. CONCLUSION: The proposed rehabilitation wheelchair can realize multi-posture transformation and balance training by the voice control system.

Efficacy and Safety of Opioids in Treating Cancer-Related Dyspnea: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials.

BACKGROUND: Dyspnea is one of the most distressing symptoms encountered by advanced cancer patients. In this study, we aimed to evaluate the role of opioids in the management of cancer-related dyspnea. METHODS: A systematic review and meta-analysis based on Randomized Controlled Trials was conducted in the databases PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials testing the effect of opioids in relieving cancer-related dyspnea. Subgroup and sensitivity analyses were performed to evaluate various types of opioids in dyspnea management and stabilization of the study respectively. RESULTS: Eleven RCTs fulfilled the eligibility criteria and had a total of 290 participants. Nine of these studies were included in meta-analyses. Compared with control, opioid therapy showed a small positive effect in dyspnea, SMD-0.82 (95%CI = -1.54 to -0.10) and Borg score, WMD-0.95 (95%CI = -1.83 to -0.06); Opioid therapy did not increase the risk of somnolence, OR0.93 (95%CI = 0.34 to 2.58), whereas a negative effect on respiratory rate was observed,WMD-1.89 (95%CI = -3.36 to -0.43); Also, there was no evidence to suggest improved performance of the 6MWT test, WMD6.49 (95%CI = -34.23 to 47.21), or the level of peripheral oxygen saturation, WMD0.33 (95%CI = -0.59 to 1.24) after opioid therapy. Subgroup analysis yielded a small positive effect for morphine on dyspnea, SMD-0.78 (95%CI = -1.45 to -0.10), whereas fentanyl showed no improvement in dyspnea, SMD-0.44 (95%CI = -0.89 to 0.02). Sensitivity analysis showed no changes in the direction of effect when any one study was excluded from the meta-analyses. CONCLUSIONS: Our systematic review and meta-analysis indicated low quality evidence for a small positive effect of opioids in cancer-related dyspnea. Evidence for safety is insufficient as comprehensive adverse events were not adequately reported in studies.

Iterative Learning Control for a Soft Exoskeleton with Hip and Knee Joint Assistance.

Walking on different terrains leads to different biomechanics, which motivates the development of exoskeletons for assisting on walking according to the type of a terrain. The design of a lightweight soft exoskeleton that simultaneously assists multiple joints in the lower limb is presented in this paper. It is used to assist both hip and knee joints in a single system, the assistance force is directly applied to the hip joint flexion and the knee joint extension, while indirectly to the hip extension also. Based on the biological torque of human walking at three different slopes, a novel strategy is developed to improve the performance of assistance. A parameter optimal iterative learning control (POILC) method is introduced to reduce the error generated due to the difference between the wearing position and the biological features of the different wearers. In order to obtain the metabolic rate, three subjects walked on a treadmill, for 10 min on each terrain, at a speed of 4 km/h under both conditions of wearing and not wearing the soft exoskeleton. Results showed that the metabolic rate was decreased with the increasing slope of the terrain. The reductions in the net metabolic rate in the experiments on the downhill, flat ground, and uphill were, respectively, 9.86%, 12.48%, and 22.08% compared to the condition of not wearing the soft exoskeleton, where their corresponding absolute values were 0.28 W/kg, 0.72 W/kg, and 1.60 W/kg.

Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis.

Purpose: X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the RS1 gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS. Methods: All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of RS1 and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions. Results: The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations. Conclusions: Patients with RS1 mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.

Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy.

BACKGROUND: Leber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD. METHODS: Retrospective consecutive case series (2010-2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis. RESULTS: We identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD. CONCLUSIONS: Our results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.